The role of the PI3K-AKT kinase pathway in T-cell development beyond the beta checkpoint.

The PI3K-AKT pathway can mediate diverse biological responses and is crucial for optimal immune responses and lymphocyte development. Deletion of PI3K subunits or AKT leads to blockage of T-cell development at the TCR-beta checkpoint. Studies with over-expression of constitutively activated AKT have implicated this pathway in anti-apoptosis of developing thymocytes and in development of regulatory T cells. However, the role of endogenous PI3K-AKT in T-cell development beyond the TCR-beta checkpoint remains unclear. Here, we inhibited the endogenous PI3K-AKT pathway in thymocytes after double negative stages by expressing the negative regulator, PTEN. These mice exhibit normal early T-cell development, but the transition from intermediate single positive to double positive (DP) thymocytes is inhibited, leading to a significantly decreased number of DP, single positive thymocytes and peripheral T cells. Proliferation of peripheral T cells is reduced but apoptosis of DP cells and subsequent T-cell maturation, including regulatory T cells, are normal. AKT phosphorylation can be readily observed in most WT T-cell compartments but not DP thymocytes in response to TCR activation. Thus, the PI3K-AKT pathway is crucial for the transition of intermediate single positive to DP thymocytes but is dispensable for apoptosis and maturation of developing thymocytes.